ABSTRACT The Washington University SPORE in Leukemia is a highly dynamic translational cancer research program that focuses specifically on leukemias and myelodysplastic syndromes (MDS). We have assembled an outstanding group of investigators with complementary expertise in basic and clinical leukemia research. In this SPORE, we leverage expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia. Our long-term goal is to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes and to develop and promote innovative translational leukemia research. To achieve these goals, the following specific aims are proposed. Aim 1. We will exploit institutional expertise in cancer genomics, immunology, and hematopoiesis to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes. Basic research at WUSM has led to the development of the following five translational research projects, all featuring innovative investigator-initiated therapeutic trials for leukemias or MDS. Project 1. Molecular determinants of decitabine responsiveness Project 2. Targeted therapies for T cell acute lymphoblastic leukemia (T-ALL) Project 3. Novel therapies for splicesome-mutant MDS Project 4. Bi-specific antibody-based therapies for AML Project 5. Memory-like NK cell augmented hematopoietic cell transplantation for AML Aim 2. We will enhance the infrastructure that supports translational leukemia research. This SPORE will support the following Shared Research Resources: 1) Core A. Biospecimen Processing; 2) Core B. Biostatistics; and 3) Core C. Administration. Aim 3. We will recruit and train new investigators in translational research. This SPORE will support a Career Enhancement Program (CEP) to recruit and mentor new investigators in translational leukemia research. The SPORE has established a successful minority post-baccalaureate training program. The SPORE also will support a Developmental Research Program (DRP) to support innovative translational concepts. Aim 4. We will facilitate inter-SPORE collaboration. Four of the SPORE projects include multi-institutional clinical trials, including three at other Leukemia SPORE institutions. We have established CEP educational exchange and grant review programs with peer Leukemia SPORE institutions. We will continue to organize and participate in joint meetings of Leukemia SPOREs at MD Anderson and Harvard.